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1.11.4 α-adrenoreceptor agonists.<br />
Agents that can stimulate α-andrenoceptors modulate a variety of physiological<br />
processes including the reduction of blood pressure, sedation and the inhibition of<br />
intestinal fluid secretion. 108 Scientists at Allergan Pharmaceuticals targeted the α –<br />
andrenoceptor to reduce intraocular pressure(IOP), a common condition in patients<br />
suffering from glaucoma. 109 The challenge in designing such agents stems from the<br />
ability of α –andrenoceptor subtypes to modulate different biological processes, most<br />
concerning are those in the central nervous system (CNS). One approach to<br />
minimizing CNS effect is topical application, minimizing access of the compound to<br />
the CNS. From the known α-andrenoceptor agonist clonidine, 110 modifications to<br />
minimize CNS access generated the lead compounds p-aminoclonidine and AGN-<br />
191103 (21) (Fig. 1.13.4). The The alternative approach is to discover compounds<br />
displaying enough selectivity between the α-andrenoceptor subtypes such that they<br />
exhibit an enhanced therapeutic index. This led to replacing the imidazolidin-imine<br />
with a 2-aminoimidazole. This compound (a) was selected for further evaluation.<br />
Binding assays demonstrated (a) bound to the α2A-receptor with a Ki = 1.7 nM and<br />
was 1200-fold selective for the α2A –receptor over the α1-receptor, 50-fold selective<br />
for the α2A –receptor over the α2B –receptor, and 10-fold selective for the α2A –<br />
receptor over the α2C –receptor. Compound (a) was found to be effective in vivo with<br />
an EC50 = 8.7 nM and importantly remained effective when administered<br />
intravenously, demonstrating its capability of crossing the blood-brain barrier.<br />
H<br />
N N<br />
NH<br />
Cl<br />
Cl<br />
H<br />
N N<br />
NH<br />
Cl<br />
Cl<br />
NH 2<br />
Clonidine p-aminoclonidine AGN-191103<br />
Fig.- 1.11.4 α-adrenoreceptor agonists.<br />
H<br />
N<br />
NH<br />
N<br />
N<br />
N<br />
H<br />
N<br />
N<br />
H<br />
N<br />
O<br />
O<br />
Compound (a)<br />
1.11.5 Anti Cancer Activity<br />
Cancer has been the leading cause of death worldwide. Chemotherapy remains one of<br />
the major treatment options available for cancer, andmost of the currently used<br />
anticancer drugs are administered to patients via a parenteral infusion or bolus<br />
injection. Clinical complications with the parenteral administrations have been